A myriad of coronary vascular functions change to accommodate the demands of exercise training. In PROJECT 4 the focus is on how microvascular exchange in healthy hearts adapts to match the metabolic demands exercise training. And whether exercise training ameliorates the effects of hyperlipidemia. The global hypothesis is that exercise-induced increases in coronary exchange capacity reflects functional changes in microvessel permeability (Ps). Ps is assessed by fluorescence microspectrofluoremetry in microvessels isolated from the hearts of pigs on a normal diet and ho a high fat (HF) diet that are sedentary (SED) and exercise trained (EX). The important finding is that following exercise training Ps responses of arterioles to vasoactive agents, such as adenosine (ADO), change in direction and magnitude. In light of these and other significant findings, the proposed work has 4 aims. Aim 1 will focus on exchange barrier pathways and Aim 2 will focus on the mechanisms by which albumin, the primary carrier of free fatty acids, in contrast to other macromolecules, traverses the walls of intact microvessels. ADO induced an NO-dependent increases in Ps in arterioles from EX pigs and a decrease in Ps of SED pig arterioles. As ADO can activate cAMP- dependent pathways and NO can activate cGMP-dependent pathways, Aim 3 will focus on the roles of cAMP and cGMP in mediating microvessel Ps. In Aim 4, we will focus on the ADO receptor subtypes which mediate ADO-induced changes in Ps in arterioles from SED and EX pigs. The data on PROJECT 4 illustrate a new role of ADO in the coordination of exchange at the level of exchange microvasculature augmenting its well known role in autoregulation of coronary blood flow. The results of this research impact both understanding solute delivery during bouts of exercise and during rest. Knowing that training influences solute flux impacts directly on the assumption that the training status of patients does not alter drug delivery or responses to the microvasculature to common mediators of coronary function.